"The U.S. Food and Drug Administration today approved the first generic versions of Celebrex (celecoxib) capsules, a treatment for rheumatoid arthritis, osteoarthritis, short-term (acute) pain, and other conditions.
Teva Pharmaceutical Indus"...
Cardiovascular Thrombotic Events
Chronic use of CELEBREX (celecoxib) may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Celecoxib) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for CELEBREX (celecoxib) 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with CELEBREX (celecoxib) 200 mg twice daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies].
All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with CELEBREX (celecoxib) , the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and CELEBREX (celecoxib) does increase the risk of serious GI events.
Two large, controlled, clinical trials of a different COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see CONTRAINDICATIONS].
As with all NSAIDs, CELEBREX (celecoxib) can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including CELEBREX (celecoxib) , should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with CELEBREX (celecoxib) and throughout the course of therapy. The rates of hypertension from the CLASS trial in the CELEBREX (celecoxib) , ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [see Clinical Studies].
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs, including CELEBREX [see ADVERSE REACTIONS]. In the CLASS study [see Clinical Studies], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX (celecoxib) 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. CELEBREX (celecoxib) should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal (GI) Effects Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including CELEBREX (celecoxib) , can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies]. With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during CELEBREX (celecoxib) therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including CELEBREX [see ADVERSE REACTIONS]. In controlled clinical trials of CELEBREX (celecoxib) , the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for CELEBREX (celecoxib) and 5% for placebo, and approximately 0.2% of patients taking CELEBREX (celecoxib) and 0.3% of patients taking placebo had notable elevations of ALT and AST.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with CELEBREX (celecoxib) . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CELEBREX (celecoxib) should be discontinued.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with CELEBREX (celecoxib) have shown renal effects similar to those observed with comparator NSAIDs.
No information is available from controlled clinical studies regarding the use of CELEBREX (celecoxib) in patients with advanced renal disease. Therefore, treatment with CELEBREX (celecoxib) is not recommended in these patients with advanced renal disease. If CELEBREX (celecoxib) therapy must be initiated, close monitoring of the patient's renal function is advisable.
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to CELEBREX (celecoxib) . In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving CELEBREX (celecoxib) . CELEBREX (celecoxib) should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see CONTRAINDICATIONS]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
CELEBREX (celecoxib) is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
In late pregnancy, starting at 30 weeks gestation, CELEBREX (celecoxib) should be avoided because it may cause premature closure of the ductus arteriosus [see Use in Specific Populations].
CELEBREX (celecoxib) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
Anemia is sometimes seen in patients receiving CELEBREX (celecoxib) . In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX (celecoxib) and 0.4% with placebo. Patients on long-term treatment with CELEBREX (celecoxib) should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. CELEBREX (celecoxib) does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages [see CLINICAL PHARMACOLOGY].
Disseminated Intravascular Coagulation (DIC)
CELEBREX (celecoxib) should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, CELEBREX (celecoxib) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, CELEBREX (celecoxib) should be discontinued.
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX (celecoxib) compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.
The pharmacological activity of CELEBREX (celecoxib) in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.
Concomitant NSAID Use
The concomitant use of CELEBREX (celecoxib) with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
Patient Counseling Information
Patients should be informed of the following information before initiating therapy with CELEBREX (celecoxib) and periodically during the course of ongoing therapy.
Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using CELEBREX (celecoxib) .
Patients should be informed that CELEBREX (celecoxib) may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. [see WARNINGS AND PRECAUTIONS].
Patients should be informed that CELEBREX (celecoxib) can lead to the onset of new hypertension or worsening of preexisting hypertension, and that CELEBREX (celecoxib) may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Patients should be informed that CELEBREX (celecoxib) can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis. [see WARNINGS AND PRECAUTIONS].
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Adverse Skin Reactions
Patients should be informed that CELEBREX (celecoxib) is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms.
Patients should be advised to stop CELEBREX (celecoxib) immediately if they develop any type of rash and contact their physician as soon as possible.
Patients with prior history of sulfa allergy should not take CELEBREX (celecoxib) [see WARNINGS AND PRECAUTIONS].
Weight Gain and Edema
Long-term administration of NSAIDs including CELEBREX (celecoxib) has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with CELEBREX (celecoxib) [see WARNINGS AND PRECAUTIONS].
Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms [see WARNINGS AND PRECAUTIONS].
Effects During Pregnancy
Patients should be informed that in late pregnancy CELEBREX (celecoxib) should be avoided because it may cause premature closure of the ductus arteriosus [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take Celebrex (celecoxib) . Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking Celebrex (celecoxib) [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment of Fertility
Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2-to 4-fold the human exposure as measured by the AUC0-24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as measured by the AUC0-24 at 200 mg twice daily) for two years.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.
Celecoxib did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11-fold human exposure at 200 mg twice daily based on the AUC0-24).
Use In Specific Populations
Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.
Celecoxib at oral doses ≥ 150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥ 30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. CELEBREX (celecoxib) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Celecoxib produced pre implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥ 50 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore, use of CELEBREX (celecoxib) during the third trimester of pregnancy should be avoided.
Labor and Delivery
Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0-24 at 200 mg BID). The effects of CELEBREX (celecoxib) on labor and delivery in pregnant women are unknown.
Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of CELEBREX (celecoxib) in breast milk. The calculated average daily infant dose was 10-40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when CELEBREX (celecoxib) is administered to a nursing woman.
CELEBREX (celecoxib) is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to CELEBREX (celecoxib) has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to CELEBREX (celecoxib) or other COX-2 selective and non-selective NSAIDs [(see BOXED WARNING and Clinical Studies].
The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including celecoxib should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see DOSAGE AND ADMINISTRATION, Animal Toxicology and Clinical Studies].
Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 substrates].
Of the total number of patients who received CELEBREX (celecoxib) in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients.
The daily recommended dose of CELEBREX (celecoxib) capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of CELEBREX (celecoxib) in patients with severe hepatic impairment is not recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
CELEBREX (celecoxib) is not recommended in patients with severe renal insufficiency [see CLINICAL PHARMACOLOGY].
Poor Metabolizers of CYP2C9 Substrates
Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e., CYP2C9*3/*3). Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 4/4/2011
This monograph has been modified to include the generic and brand name in many instances.
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